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Tofranil-PM

"Everyone occasionally feels blue or sad. But these feelings are usually short-lived and pass within a couple of days. When you have depression, it interferes with daily life and causes pain for both you and those who care about you. Depression is"...

Tofranil-PM

Warnings
Precautions

WARNINGS

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for imipramine pamoate should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that imipramine pamoate is not approved for use in treating bipolar depression.

Extreme caution should be used when this drug is given to patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes, and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug; patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug's anticholinergic properties; hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity; patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold; patients receiving guanethidine, clonidine, or similar agents, since imipramine pamoate may block the pharmacologic effects of these drugs; patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of imipramine pamoate, downward dosage adjustment of imipramine pamoate may be required when given concomitantly with methylphenidate hydrochloride.

Since imipramine pamoate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.

Tofranil-PM may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol (see PRECAUTIONS).

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Tofranil-PM, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Tofranil-PM with MAOIs intended to treat psychiatric disorders is contraindicated. Tofranil-PM should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Tofranil-PM. Tofranil-PM should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

If concomitant use of Tofranil-PM with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Tofranil-PM and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

PRECAUTIONS

General

An ECG recording should be taken prior to the initiation of larger-than-usual doses of imipramine pamoate and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. See WARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of imipramine pamoate. It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with imipramine pamoate and may require hospitalization. Prescriptions should be written for the smallest amount feasible.

Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, imipramine pamoate may be resumed in lower dosage when these episodes are relieved.

Administration of a tranquilizer may be useful in controlling such episodes. An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine.

Concurrent administration of imipramine pamoate with electroshock therapy may increase the hazards: such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.

Patients taking imipramine pamoate should avoid excessive exposure to sunlight since there have been reports of photosensitization.

Both elevation and lowering of blood sugar levels have been reported with imipramine pamoate use.

Imipramine pamoate should be used with caution in patients with significantly impaired renal or hepatic function.

Patients who develop a fever and a sore throat during therapy with imipramine pamoate should have leukocyte and differential blood counts performed.

Imipramine pamoate should be discontinued if there is evidence of pathological neutrophil depression.

Prior to elective surgery, imipramine pamoate should be discontinued for as long as the clinical situation will allow.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine pamoate and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for imipramine pamoate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking imipramine pamoate.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Pregnancy

Animal reproduction studies have yielded inconclusive results (see also Animal Pharmacology & Toxicology).

There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus.

Nursing Mothers

Limited data suggest that imipramine is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk).

It is generally recommended that Tofranil-PM should not be used in children because of the increased potential for acute overdosage due to the high unit potency (75 mg, 100 mg, 125 mg, and 150 mg). Each capsule contains imipramine pamoate equivalent to 75 mg, 100 mg, 125 mg, or 150 mg imipramine hydrochloride. Anyone considering the use of imipramine pamoate in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

In the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with Tofranil™, brand of imipramine hydrochloride tablets, in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly.

Clinical studies of Tofranil™, brand of imipramine hydrochloride tablets, in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (see also DOSAGE AND ADMINISTRATION in Adolescent and Geriatric Patients) (see also PRECAUTIONS, General)

Last reviewed on RxList: 12/7/2012
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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